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Abstract Ethical review systems need to build on their experiences of COVID-19 research to enhance their preparedness for future pandemics. Recommendations from representatives from over twenty countries include: improving relationships across the research ecosystem; demonstrating willingness to reform and adapt systems and processes; and making the case robustly for better resourcing.

OBJECTIVES/GOALS: Harmful algal blooms (HABs) are increasing in both frequency and intensity due to climate change. HABs release the toxin microcystin-LR (MC-LR) which enters cells via organic anion-transporting polypeptides (OATPs). In this study, we sought to assess the ability of MC-LR to accumulate in trophoblasts, potentially disrupting placental functions. METHODS/STUDY POPULATION: Intracellular accumulation of MC-LR at exposure concentrations of 0.1, 1, and 10 µM over 6 hrs was evaluated in immortalized JAR placental cytotrophoblasts. Western blotting was used to evaluate protein-bound MC-LR accumulation in JAR cells. The function of OATP transporters in JAR cells was determined by pre-incubating cells with 10µM cyclosporin A, a general OATP inhibitor for 1 hr, and then incubated with 1µM OATP substrate fluorescein for up to 40 min. Fluorescence of fluorescein was measured at Ex/Em: 494nm/515nm by spectrophotometry. RESULTS/ANTICIPATED RESULTS: A concentration-dependent increase of MC-LR bound proteins in JAR cells was observed at 6 hrs with the greatest intracellular accumulation of MC-LR at 10µM. In the transporter experiments, a significant decrease of fluorescein uptake by up to 45% into JAR cells was observed following cyclosporin A inhibition of OATPs. These findings are consistent with the functional expression of OATP transporters in JAR placenta cells. Ongoing studies are evaluating whether the cyclosporin A-mediated inhibition of OATPs also inhibits the uptake of MC-LR. DISCUSSION/SIGNIFICANCE: Although MC-LR is well-known for its hepatotoxic and neurotoxic effects, there is growing interest in examining its potential adverse impacts on female reproductive health, particularly during pregnancy. Active uptake of MC-LR into the placenta could interfere with placental and fetal development.

Brake wear particles are generated through frictional contact between the brake disc or brake drum and the brake pads. Some of these particles may be released into the atmosphere, contributing to airborne fine particulate matter (PM2.5). In this study, an onboard system was developed and tested to measure brake wear particles emitted under real-world driving conditions. Brake wear particles were extracted from a fixed volume enclosure surrounding the pad and disc installed on the front wheel of a light-duty vehicle. Real-time data on size distribution, number concentration, PM2.5 mass, and the contribution of semi-volatiles were obtained via a suite of instruments sub-sampling from the constant volume sampler (CVS) dilution tunnel. Repeat measurements of brake particles were obtained from a 42 min bespoke drive cycle on a chassis dynamometer, from on-road tests in an urban area, and from braking events on a test track. The results showed that particle emissions coincided with braking events, with mass emissions around 1 mg/km/brake during on-road driving. Particle number emissions of low volatility particles were between 2 and 5 × 109 particles/km/brake. The highest emissions were observed under more aggressive braking. The project successfully developed a proof-of-principle measurement system for brake wear emissions from transient vehicle operation. The system shows good repeatability for stable particle metrics, such as non-volatile particle number (PN) from the solid particle counting system (SPCS), and allows for progression to a second phase of work where emissions differences between commercially available brake system components will be assessed.

Ludwig Wittgenstein’s relation to Gestalt Psychology is typically understood through the lens of his engagement with Wolfgang Köhler’s work. Though valuable, this framing may obscure certain broader points of similarity between Wittgenstein’s methodological approach and the Gestalt school considered as a whole. In what follows I pursue this line of thought by comparing Wittgenstein’s discussion of rule-following in the Philosophical Investigations with Max Wertheimer’s concept of productive thinking. I argue that Wertheimer’s emphasis on the shared and public aspects of Gestalt phenomena counteracts Köhler’s tendency to characterise Gestalts as essentially private entities. I suggest that in this respect at least, Wertheimer’s approach is closer than Köhler’s to Wittgenstein’s later philosophical orientation.

Cessation of one component of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) has been associated with increased risk of ischemic events but it is uncertain whether discontinuation of aspirin is preferable to discontinuation of the oral P2Y12 inhibitor. The GLOBAL LEADERS study compared two antiplatelet strategies following PCI, cessation of aspirin at 1 month with continued ticagrelor monotherapy for 23 months versus standard DAPT for 12 months followed by aspirin monotherapy for a further 12 months. We assessed recovery of platelet reactivity after withdrawal of either aspirin or ticagrelor at 1 month and 12 months, respectively, in this study. Platelet aggregation (PA) was assessed before cessation of DAPT (‘baseline’) and after 2, 7, and 14 days post-cessation using Multiplate whole-blood aggregometry with collagen, thrombin-receptor-activating peptide (TRAP), adenosine diphosphate (ADP) and arachidonic acid (AA) as agonists. Following cessation of aspirin at 1 month, there was marked recovery of PA induced by AA (baseline [mean ± SD]: 11.1 ± 7.4 U vs. 14 days: 64.9 ± 19.6 U, p

Background and importance: Chest pain (CP) is one of the most frequent presentations to the emergency department (ED), a large proportion of which is non-cardiac chest pain (NCCP). Repeat attendances to ED are common and impose considerable burden to overstretched departments. Objective: Our aim was to determine drivers for repeat ED presentations using NCCP as the primary cause of index presentation. Design, setting and participants: This was a retrospective cohort study of 1066 consecutive presentations with NCCP to a major urban hospital ED in North England. Index of Multiple Deprivation (IMD), a postcode-derived validated index of deprivation, was computed. Charlson comorbidity index (CCI) was determined by reference to known comorbidity variables. Repeat presentation to ED to any national hospital was determined by a national linked database (population 53.5 million). Independent predictors of ED representation were computed using logistic regression analysis. Results: Median age was 43 (IQR 28–59), and 50.8% were male. Furthermore, 27.8%, 8.1% and 3.8% suffered from chronic obstructive pulmonary disease (COPD), hypertension and diabetes mellitus, respectively. The most frequent diagnoses, using ICD-10 coding, were non-cardiac chest pain (55.1%), followed by respiratory conditions (14.7%). One-year incidence of adjudicated myocardial infarction, urgent or emergency coronary revascularisation and all-cause death was 0.6%, 2% and 5.3%, respectively. There was a total of 4770 ED repeat presentations 1 year prior to or following index presentation with NCCP in this cohort. Independent (multivariate) predictors for frequent re-presentation (defined as ≥2 representations) were a history of COPD (OR [odds ratio] 2.06, p = 0.001), previous MI (OR3.6, p = 0.020) and a Charlson comorbidity index ≥1 (OR 1.51, p = 0.030). The frequency of previous MI was low as only 3% had sustained a previous MI. Conclusions: This analysis indicates that COPD and complex health care needs (represented by high CCI), but not socio-economic deprivation, should be health policy targets for lessening repeat ED presentations. What is already known on this topic: Repeat presentations with non-ischaemic chest pain are common, placing a considerable burden on emergency departments. What this study adds: COPD and complex health care needs, denoted by Charlson comorbidity index, are implicated as drivers for repeat presentation to accident and emergency department. Socio-economic deprivation was not an independent predictor of re-presentation. How might this study affect research, practice, or policy: Community-based support for COPD and complex health care needs may reduce frequency of ED attendance.

Abstract Background Global progress towards reducing tuberculosis (TB) incidence and mortality has consistently lagged behind the World Health Organization targets leading to a perception that large reductions in TB burden cannot be achieved. However, several recent and historical trials suggest that intervention efforts that are comprehensive and intensive can have a substantial epidemiological impact. We aimed to quantify the potential epidemiological impact of an intensive but realistic, community-wide campaign utilizing existing tools and designed to achieve a “step change” in the TB burden. Methods We developed a compartmental model that resembled TB transmission and epidemiology of a mid-sized city in India, the country with the greatest absolute TB burden worldwide. We modeled the impact of a one-time, community-wide screening campaign, with treatment for TB disease and preventive therapy for latent TB infection (LTBI). This one-time intervention was followed by the strengthening of the tuberculosis-related health system, potentially facilitated by leveraging the one-time campaign. We estimated the tuberculosis cases and deaths that could be averted over 10 years using this comprehensive approach and assessed the contributions of individual components of the intervention. Results A campaign that successfully screened 70% of the adult population for active and latent tuberculosis and subsequently reduced diagnostic and treatment delays and unsuccessful treatment outcomes by 50% was projected to avert 7800 (95% range 5450–10,200) cases and 1710 (1290–2180) tuberculosis-related deaths per 1 million population over 10 years. Of the total averted deaths, 33.5% (28.2–38.3) were attributable to the inclusion of preventive therapy and 52.9% (48.4–56.9) to health system strengthening. Conclusions A one-time, community-wide mass campaign, comprehensively designed to detect, treat, and prevent tuberculosis with currently existing tools can have a meaningful and long-lasting epidemiological impact. Successful treatment of LTBI is critical to achieving this result. Health system strengthening is essential to any effort to transform the TB response.

Background: Locked posterior glenohumeral dislocations are a rare but often missed injury when it occurs. In these dislocations, patients may have a reverse Hill–Sachs lesion, which are associated with high rates of recurrent posterior glenohumeral instability. Open reduction with allograft reconstruction to reconstruct the defect can be used to treat chronic locked posterior glenohumeral dislocations. Indications: Osteochondral allograft reconstruction is indicated when patients have a large defect affecting less than 50% of the articular surface and if the humeral head has been dislocated for less than 6 months. Technique Description: With the patient in beach chair position, exposure is obtained through deltopectoral approach. An open reduction is performed, and the defect is debrided down to healthy bleeding bone. The defect is templated, and the allograft is harvested and prepared. The allograft is securely fixed using cannulated cancellous screws. The patient undergoes a postoperative rehabilitation protocol. Results: There have been several case series following allograft reconstruction for locked posterior dislocations that have demonstrated good results. Riff et al found favorable results in his series of 20 patients with isolated humeral head lesions, with significant improvement in patient-outcome measures. There are several potential complications though. A systematic review by Saltzman et al found allograft resorption to occur in 36% and glenohumeral arthritic changes to occur in 35% with frozen allografts. These rates appear to be improved with fresh allografts. Discussion/Conclusion: In conclusion, osteochondral allograft is an effective surgical treatment for large Hill–Sachs defects in chronic locked posterior dislocations.

Abstract Background Modelling and simulation are being increasingly utilized to support the discovery and development of new anti-malarial drugs. These approaches require reliable in vitro data for physicochemical properties, permeability, binding, intrinsic clearance and cytochrome P450 inhibition. This work was conducted to generate an in vitro data toolbox using standardized methods for a set of 45 anti-malarial drugs and to assess changes in physicochemical properties in relation to changing target product and candidate profiles. Methods Ionization constants were determined by potentiometric titration and partition coefficients were measured using a shake-flask method. Solubility was assessed in biorelevant media and permeability coefficients and efflux ratios were determined using Caco-2 cell monolayers. Binding to plasma and media proteins was measured using either ultracentrifugation or rapid equilibrium dialysis. Metabolic stability and cytochrome P450 inhibition were assessed using human liver microsomes. Sample analysis was conducted by LC–MS/MS. Results Both solubility and fraction unbound decreased, and permeability and unbound intrinsic clearance increased, with increasing Log D7.4. In general, development compounds were somewhat more lipophilic than legacy drugs. For many compounds, permeability and protein binding were challenging to assess and both required the use of experimental conditions that minimized the impact of non-specific binding. Intrinsic clearance in human liver microsomes was varied across the data set and several compounds exhibited no measurable substrate loss under the conditions used. Inhibition of cytochrome P450 enzymes was minimal for most compounds. Conclusions This is the first data set to describe in vitro properties for 45 legacy and development anti-malarial drugs. The studies identified several practical methodological issues common to many of the more lipophilic compounds and highlighted areas which require more work to customize experimental conditions for compounds being designed to meet the new target product profiles. The dataset will be a valuable tool for malaria researchers aiming to develop PBPK models for the prediction of human PK properties and/or drug–drug interactions. Furthermore, generation of this comprehensive data set within a single laboratory allows direct comparison of properties across a large dataset and evaluation of changing property trends that have occurred over time with changing target product and candidate profiles.

This study focused on optimizing the placement of shortwave infrared (SWIR) bands for pixel-level estimation of fractional crop residue cover (fR) for the upcoming Landsat Next mission. We applied an iterative wavelength shift approach to a database of crop residue field spectra collected in Beltsville, Maryland, USA (n = 916) and computed generalized two- and three-band spectral indices for all wavelength combinations between 2000 and 2350 nm, then used these indices to model field-measured fR. A subset of the full dataset with a Normalized Difference Vegetation Index (NDVI) < 0.3 threshold (n = 643) was generated to evaluate green vegetation impacts on fR estimation. For the two-band wavelength shift analyses applied to the NDVI < 0.3 dataset, a generalized normalized difference using 2226 nm and 2263 nm bands produced the top fR estimation performance (R2 = 0.8222; RMSE = 0.1296). These findings were similar to the established two-band Shortwave Infrared Normalized Difference Residue Index (SINDRI) (R2 = 0.8145; RMSE = 0.1324). Performance of the two-band generalized normalized difference and SINDRI decreased for the full-NDVI dataset (R2 = 0.5865 and 0.4144, respectively). For the three-band wavelength shift analyses applied to the NDVI < 0.3 dataset, a generalized ratio-based index with a 2031–2085–2216 nm band combination, closely matching established Cellulose Absorption Index (CAI) bands, was top performing (R2 = 0.8397; RMSE = 0.1231). Three-band indices with CAI-type wavelengths maintained top fR estimation performance for the full-NDVI dataset with a 2036–2111–2217 nm band combination (R2 = 0.7581; RMSE = 0.1548). The 2036–2111–2217 nm band combination was also top performing in fR estimation (R2 = 0.8690; RMSE = 0.0970) for an additional analysis assessing combined green vegetation cover and surface moisture effects. Our results indicate that a three-band configuration with band centers and wavelength tolerances of 2036 nm (±5 nm), 2097 nm (±14 nm), and 2214 (±11 nm) would optimize Landsat Next SWIR bands for fR estimation.

Within the Australian beef industry bovine respiratory disease is considered one of the most common disease and costs the industry an average net loss of $1647.53 Australian dollars per animal death to bovine respiratory disease complex (BRD). This is due to the disease overwhelming the animal’s immune system during a period where they experience multiple stressors that consequently increase the animal’s susceptivity to disease. Research into the bioactive compounds commonly found in marine algae is rapidly increasing due to its positive health benefits and potential immune modulating properties. Algal supplementation within previous studies has resulted in improved reproduction potential, growth performance, increases antioxidant activity and decreased proinflammatory cytokine concentrations. Additional research is required to further understand the aetiology of BRD and complete analysis of the bioavailability of these bioactive compounds within marine algae to fully explore the potential of marine algae supplementation.

The domestic rock pigeon (Columba livia) is among the most widely distributed and phenotypically diverse avian species. C. livia is broadly studied in ecology, genetics, physiology, behavior, and evolutionary biology, and has recently emerged as a model for understanding the molecular basis of anatomical diversity, the magnetic sense, and other key aspects of avian biology. Here we report an update to the C. livia genome reference assembly and gene annotation dataset. Greatly increased scaffold lengths in the updated reference assembly, along with an updated annotation set, provide improved tools for evolutionary and functional genetic studies of the pigeon, and for comparative avian genomics in general.

Abstract Background Obesity is emerging as a global health problem, with more than one-third of the world’s adult population being overweight or obese. In this study, we investigated worldwide population differentiation in allele frequencies of obesity-associated SNPs (single nucleotide polymorphisms). Results We collected a total of 225 obesity-associated SNPs from a public database. Their population-level allele frequencies were derived based on the genotype data from 1000 Genomes Project (phase 3). We used hypergeometric model to assess whether the effect allele at a given SNP is significantly enriched or depleted in each of the 26 populations surveyed in the 1000 Genomes Project with respect to the overall pooled population. Our results indicate that 195 out of 225 SNPs (86.7%) possess effect alleles significantly enriched or depleted in at least one of the 26 populations. Populations within the same continental group exhibit similar allele enrichment/depletion patterns whereas inter-continental populations show distinct patterns. Among the 225 SNPs, 15 SNPs cluster in the first intron region of the FTO gene, which is a major gene associated with body-mass index (BMI) and fat mass. African populations exhibit much smaller blocks of LD (linkage disequilibrium) among these15 SNPs while European and Asian populations have larger blocks. To estimate the cumulative effect of all variants associated with obesity, we developed the personal composite genetic risk score for obesity. Our results indicate that the East Asian populations have the lowest averages of the composite risk scores, whereas three European populations have the highest averages. In addition, the population-level average of composite genetic risk scores is significantly correlated (R2 = 0.35, P = 0.0060) with obesity prevalence. Conclusions We have detected substantial population differentiation in allele frequencies of obesity-associated SNPs. The results will help elucidate the genetic basis which may contribute to population disparities in obesity prevalence.

Background: Precision medicine is the Holy Grail of interventions that are tailored to a patient’s individual characteristics. However, conventional clinical trials are designed to find differences in averages, and interpreting these differences depends on untestable assumptions. Although only an ideal, a constant effect of treatment would facilitate individual management. A direct consequence of a constant effect is that the variance of the outcome measure would be the same in the treated and control arms. We reviewed the literature to explore the similarity of these variances as a foundation for examining whether and how often precision medicine is definitively required. Methods: We reviewed parallel clinical trials with numerical primary endpoints published in 2004, 2007, 2010 and 2013. We collected the baseline and final standard deviations of the main outcome measure. We assessed homoscedasticity by comparing the variance of the primary endpoint between arms through the outcome variance ratio (treated to control group). Results: The review provided 208 articles with enough information to conduct the analysis. One out of five studies (n = 40, 19.2%) had statistically different variances between groups, implying a non-constant-effect. The adjusted point estimate of the mean outcome variance ratio (treated to control group) is 0.89 (95% CI 0.81 to 0.97). Conclusions: The mean variance ratio is significantly lower than 1 and the lower variance was found more often in the intervention group than in the control group, suggesting it is more usual for treated patients to be stable. This observed reduction in variance might also imply that there could be a subgroup of less ill patients who derive no benefit from treatment. This would require further study as to whether the treatment effect outweighs the side effects as well as the economic costs. We have shown that there are ways to analyze the apparently unobservable constant effect.

Background: Precision medicine is the Holy Grail of interventions that are tailored to a patient’s individual characteristics. However, conventional clinical trials are designed to find differences in averages, and interpreting these differences depends on untestable assumptions. Although ideal, a constant effect would facilitate individual management. Another consequence of a constant effect is that the outcome variance would be the same in treated and control arms. We reviewed the literature to explore the similarity of these variances as a foundation for examining whether and how often precision medicine is definitively needed. Methods: We reviewed parallel trials with quantitative outcomes published in 2004, 2007, 2010 and 2013. We collected baseline and final standard deviations of the main outcome. We assessed homoscedasticity by comparing the variance of the primary endpoint between arms through the outcome variance ratio (treated to control group). Results: The review provided 208 articles with enough information to conduct the analysis. One out of seven studies (n = 30, 14.4%) had statistically different variances between groups, leading a non-constant-effect. The adjusted point estimate of the mean outcome variance ratio (treated to control group) is 0.89 (95% CI 0.81 to 0.97). Conclusions: We found that the outcome variance was more often smaller in the intervention group, suggesting that treated patients may end up pertaining more often to reference values. This observed reduction in variance might also imply that there could be a subgroup of less ill patients who derive no benefit, which would require studying whether the effect merits enduring the side effects as well as the economic costs. We have shown that the comparison of variances is a useful but not definitive tool for assessing whether or not the assumption of a constant effect holds.

We determine the (refined) Nash equilibria for a bounded rational Carfi'-Musolino speculative and hedging model. This model shows two types of operators: a real economic subject (Air) and one or more investment banks (Bank). We consider the bank agents' behavior to equilibrate much more quickly than that of Air, as they react to the move of Air. In this sense, Air is an acting external agent, whereas the action of the banks is `annealed' - i.e., equilibrates before Air makes its next transaction. When Air makes no purchases of oil futures as a hedge, two Nash equilibria exist for the bank agents. However, a unique Nash equilibrium exists for the bank agents when Air makes a purchase. This is a result of Air's purchase breaking a symmetry of the potential. The existence of multiple equilibriums in this two-market model is in the spirit of the Sonnenschein-Mantel-Debreu theorem, and is associated with phase transitions in statistical mechanics.

Background: Insulin is generally administered to people with type 1 diabetes mellitus (T1DM) using multiple daily injections (MDIs), but can also be delivered using infusion pumps. In the UK, pumps are recommended for patients with the greatest need and adult use is less than in comparable countries. Previous trials have been small, of short duration and have failed to control for training in insulin adjustment. Objective: To assess the clinical effectiveness and cost-effectiveness of pump therapy compared with MDI for adults with T1DM, with both groups receiving equivalent structured training in flexible insulin therapy. Design: Pragmatic, multicentre, open-label, parallel-group cluster randomised controlled trial, including economic and psychosocial evaluations. After participants were assigned a group training course, courses were randomly allocated in pairs to either pump or MDI. Setting: Eight secondary care diabetes centres in the UK. Participants: Adults with T1DM for > 12 months, willing to undertake intensive insulin therapy, with no preference for pump or MDI, or a clinical indication for pumps. Interventions: Pump or MDI structured training in flexible insulin therapy, followed up for 2 years. MDI participants used insulin analogues. Pump participants used a Medtronic Paradigm® VeoTM (Medtronic, Watford, UK) with insulin aspart (NovoRapid, Novo Nordisk, Gatwick, UK). Main outcome measures: Primary outcome – change in glycated haemoglobin (HbA1c) at 2 years in participants whose baseline HbA1c was ≥ 7.5% (58 mmol/mol). Key secondary outcome – proportion of participants with HbA1c ≤ 7.5% at 2 years. Other outcomes at 6, 12 and 24 months – moderate and severe hypoglycaemia; insulin dose; body weight; proteinuria; diabetic ketoacidosis; quality of life (QoL); fear of hypoglycaemia; treatment satisfaction; emotional well-being; qualitative interviews with participants and staff (2 weeks), and participants (6 months); and ICERs in trial and modelled estimates of cost-effectiveness. Results: We randomised 46 courses comprising 317 participants: 267 attended a Dose Adjustment For Normal Eating course (132 pump; 135 MDI); 260 were included in the intention-to-treat analysis, of which 235 (119 pump; 116 MDI) had baseline HbA1c of ≥ 7.5%. HbA1c and severe hypoglycaemia improved in both groups. The drop in HbA1c% at 2 years was 0.85 on pump and 0.42 on MDI. The mean difference (MD) in HbA1c change at 2 years, at which the baseline HbA1c was ≥ 7.5%, was –0.24% [95% confidence interval (CI) –0.53% to 0.05%] in favour of the pump (p = 0.098). The per-protocol analysis showed a MD in change of –0.36% (95% CI –0.64% to –0.07%) favouring pumps (p = 0.015). Pumps were not cost-effective in the base case and all of the sensitivity analyses. The pump group had greater improvement in diabetes-specific QoL diet restrictions, daily hassle plus treatment satisfaction, statistically significant at 12 and 24 months and supported by qualitative interviews. Limitation: Blinding of pump therapy was not possible, although an objective primary outcome was used. Conclusion: Adding pump therapy to structured training in flexible insulin therapy did not significantly enhance glycaemic control or psychosocial outcomes in adults with T1DM. Research priority: To understand why few patients achieve a HbA1c of

We characterized in vivo a functional superparamagnetic iron-oxide magnetic resonance contrast agent that shortens the T2 relaxation time in magnetic resonance imaging (MRI) of prostate cancer xenografts. The agent was developed by conjugating Molday ION™ carboxyl-6 (MIC6), with a deimmunized mouse monoclonal antibody (muJ591) targeting prostate-specific membrane antigen (PSMA). This functional contrast agent could be used as a noninvasive method to detect prostate cancer cells that are PSMA positive and more readily differentiate them from surrounding tissues for treatment. The functional contrast agent was injected intravenously into mice and its effect was compared to both MIC6 (without conjugated antibody) and phosphate-buffered saline (PBS) injection controls. MR imaging was performed on a clinical 3T MRI scanner using a multiecho spin echo (MESE) sequence to obtain T2 relaxation time values. Inductively coupled plasma atomic emission spectroscopy was used to confirm an increase in elemental iron in injected mice tumours relative to controls. Histological examination of H&E stained tissues showed normal morphology of the tissues collected.

Introduction: Emergency physicians (EPs) are reported to have a higher rate of substance use disorder (SUD) than most specialties, although little is known about their prognosis. We examined the outcomes of emergency physician compared to other physicians in the treatment of substance use disorders in Physician Health Programs (PHP). Methods: This study used the dataset from a 5-year, longitudinal, cohort study involving 904 physicians with diagnoses of SUD consecutively admitted to one of 16 state PHPs between 1995 and 2001. We compared 56 EPs to 724 other physicians. Main outcome variables were rates of relapse, successful completion of monitoring, and return to clinical practice. Results: EPs had a higher than expected rate of SUD (odds ratio [OR] 2.7 confidence interval [CI]: 2.1–3.5, p,0.001). Half of each group (49% of EPs and 50% of the others) enrolled in a PHP due to alcohol-related problems. Over a third of each group (38% of EPs and 34% of the others) enrolled due to opioid use. During monitoring by the PHPs, 13% of EPs had at least one positive drug test compared to 22% of the other physicians; however, this difference was not significant (p¼0.13). At the end of the 5-year follow-up period, 71% of EPs and 64% of other physicians had completed their contracts and were no longer required to be monitored (OR 1.4 [CI: 0.8-2.6], p ¼ 0.31). The study found that the proportion of EPs (84%) continuing their medical practice was generally as high as that of other physicians (72%) (OR 2.0 [CI: 1.0–4.1], p ¼ 0.06). Conclusion: In the study EPs did very well in the PHPs with an 84% success rate in completion and return to clinical practice at 5 years. Of the 3 outcome variables measured, rates of relapse, successful completion of monitoring, and return to clinical practice, EPs had a high rate of success on all variables compared to the other physician cohort. These data support the conclusion that EM physicians do well following treatment of SUD with monitoring in PHPs and generally return to the practice of emergency medicine. [West J Emerg Med. 2014;15(1):20–25.]

Background and design: This research was based on a reanalysis of a merged data set from two intermediate care (IC) projects in order to identify patient characteristics associated with outcomes [Nancarrow SA, Enderby PM, Moran AM, Dixon S, Parker SG, Bradburn MJ, et al. The Relationship Between Workforce Flexibility and the Costs and Outcomes of Older Peoples’ Services (COOP). Southampton: National Institute for Health Research (NIHR) Service Delivery and Organisation (SDO); 2010 and Nancarrow SA, Enderby PM, Ariss SM, Smith T, Booth A, Campbell MJ, et al. The Impact of Enhancing the Effectiveness of Interdisciplinary Working (EEICC). Southampton: NIHR SDO; 2012]. Additionally, the impact of different team and staffing structures on patient outcomes and service costs was examined, when possible given the data sets, to enable identification of the most cost-effective service configurations and change over time with service provision. This secondary analysis was placed within updated literature reviews focused on the separate questions. Research objectives: (1) To identify those patients most likely to benefit from IC and those who would be best placed to receive care elsewhere; (2) to examine the effectiveness of different models of IC; (3) to explore the differences between IC service configurations and how they have changed over time; and (4) to use the findings above to develop accessible evidence to guide service commissioning and monitoring. Setting: Community-based services for older people are described in many different ways, among which are IC services and community rehabilitation. For the purposes of this report we call the services IC services and include all community-based provision for supporting older people who would otherwise be admitted to hospital or who would require increased length of stay in hospital (e.g. hospital at home schemes, post-acute care, step-up and step-down services). Participants: The combined data set contained data on 8070 patient admissions from 32 IC teams across England and included details of the service context, costs, staffing/skill mix (800 staff), patient health status and outcomes. Interventions: The interventions associated with the study cover the range of services and therapies available in IC settings. These are provided by a wide range of professionals and care staff, including nursing, allied health and social care. Outcome measures: (1) Service data – each team provided information relating to the size, nature, staffing and resourcing of the services. Data were collected on a service pro forma. (2) Team data – all staff members of the teams participating in both studies provided individual information using the Workforce Dynamics Questionnaire. (3) Patient data – patient data were collected on admission and discharge using a client record pack. The client record pack recorded a range of data utilising a number of validated tools, such as demographic data, level of care (LoC) data, therapy outcome measure (TOM) scale, European Quality of Life-5 Dimensions (EQ-5D) questionnaire and patient satisfaction survey. Results: (1) The provision of IC across England is highly variable with different referral routes, team structures, skill mix and cost-effectiveness; (2) in more recent years, patients referred to IC have more complex needs associated with more severe impairments; (3) patients most likely to improve were those requiring rehabilitation as determined by levels 3, 4 and 5 on the LoC (> 40% for impairment, activity and participation, and > 30% for well-being as determined on the TOM scale); (4) half of all patients with outcome data improved on at least one of the domains of the TOM scale; (5) for every 10-year increase in age there was a 6% decrease in the odds of returning home. The chance of remaining or returning home was greater for females than males; (6) a high percentage of patients referred to IC do not require the service; and (7) teams including clinical support staff and domiciliary staff were associated with a small relative improvement in TOM impairment scores when compared with other teams. Conclusions: This study provides additional evidence that interdisciplinary teamworking in IC may be associated with better outcomes for patients, but care should be taken with overinterpretation. The measures that were used within the studies were found to be reliable, valid and practical and could be used for benchmarking. This study highlights the need for funding high-quality studies that attempt to examine what specific team-level factors are associated with better outcomes for patients. It is therefore important that studies in the future attempt empirically to examine what process-level team variables are associated with these outcomes. Funding: The NIHR Health Services and Delivery Research programme.

We present the de novo draft genome sequence for a vertebrate mammalian herbivore, the desert woodrat (Neotoma lepida). This species is of ecological and evolutionary interest with respect to ingestion, microbial detoxification and hepatic metabolism of toxic plant secondary compounds from the highly toxic creosote bush (Larrea tridentata) and the juniper shrub (Juniperus monosperma). The draft genome sequence and annotation have been deposited at GenBank under the accession LZPO01000000.

In this study we developed, characterized and validated in vitro a functional superparagmagnetic iron-oxide based magnetic resonance contrast agent by conjugating a commercially available iron oxide nanoparticle, Molday ION Rhodamine-B Carboxyl (MIRB), with a deimmunized mouse monoclonal antibody (muJ591) targeting prostate-specific membrane antigen (PSMA). This functional contrast agent is intended for the specific and non-invasive detection of prostate cancer cells that are PSMA positive, a marker implicated in prostate tumor progression and metastasis. The two-step carbodiimide reaction used to conjugate the antibody to the nanoparticle was efficient and we obtained an elemental iron content of 1958 ± 611 per antibody. Immunofluorescence microscopy and flow cytometry showed that the conjugated muJ591:MIRB complex specifically binds to PSMA-positive (LNCaP) cells. The muJ591:MIRB complex reduced cell adhesion and cell proliferation on LNCaP cells and caused apoptosis as tested by Annexin V assay, suggesting anti-tumorigenic characteristics. Measurements of the T2 relaxation time of the muJ591:MIRB complex using a 400 MHz Innova NMR and a multi-echo spin-echo sequence on a 3T MRI (Achieva, Philips) showed a significant T2 relaxation time reduction for the muJ591:MIRB complex, with a reduced T2 relaxation time as a function of the iron concentration. PSMA-positive cells treated with muJ591:MIRB showed a significantly shorter T2 relaxation time as obtained using a 3T MRI scanner. The reduction in T2 relaxation time for muJ591:MIRB, combined with its specificity against PSMA+LNCaP cells, suggest its potential as a biologically-specific MR contrast agent.

Telerehabilitation refers to the delivery of rehabilitation services via information and communication technologies. Clinically, this term encompasses a range of rehabilitation and habilitation services that include assessment, monitoring, prevention, intervention, supervision, education, consultation, and counseling. Telerehabilitation has the capacity to provide service across the lifespan and across a continuum of care. Just as the services and providers of telerehabilitation are broad, so are the points of service, which may include health care settings, clinics, homes, schools, or community-based worksites. This document was developed collaboratively by members of the Telerehabilitation SIG of the American Telemedicine Association, with input and guidance from other practitioners in the field, strategic stakeholders, and ATA staff. Its purpose is to inform and assist practitioners in providing effective and safe services that are based on client needs, current empirical evidence, and available technologies. Telerehabilitation professionals, in conjunction with professional associations and other organizations are encouraged to use this document as a template for developing discipline-specific standards, guidelines, and practice requirements.

This pilot study of a school-based telepractice pilot project in a rural, remote county of North Carolina investigated the satisfaction of parents/caregivers, teachers, and administrators with a year-long telespeech therapy program delivered by a university clinic. Upon completion of the almost year-long project, a satisfaction survey incorporating a 5-point equal-appearing Likert scale (1= strongly disagree; 5= strongly agree) was disseminated to the stakeholders. The results sorted by the three populations surveyed, indicated stakeholder satisfaction with student progress toward their speech and language goals, and clinician accessibility and responsiveness (mean ratings > 4 points). The respondents (N=23) also indicated they would “recommend TeleSpeech Therapy to other school districts” (mean rating: 4.3). The only mean rating below 4.0 was associated with teacher responses to the statement: “My expectations for the TeleSpeech Therapy program have been met” (mean rating: 3.92). Overall, parents/caregivers, teachers, and administrators appeared to find telepractice a satisfactory service delivery model for school-based speech-language therapy.

Background: Precision medicine is the Holy Grail of interventions that are tailored to a patient’s individual characteristics. However, conventional clinical trials are designed to find differences with the implicit assumption that the effect is the same in all patients within the eligibility criteria. If this were the case, then there would be no grounds for treating different patients differently. One consequence of the assumption is that the variance in the outcome variable would be the same in treated and control arms. We reviewed the literature to see if this were the case and so to see how often precision medicine would not be useful. Methods: We reviewed parallel trials with quantitative outcomes published in 2004, 2007, 2010 and 2013. We collected baseline and final standard deviations of the main outcome. We assessed homoscedasticity by comparing the variance of the primary endpoint between arms through the outcome variance ratio (treated to control group). Results: The review provided 208 articles with enough information to conduct the analysis. One out of seven studies (n = 30, 14.4%) had statistically different variances between groups, leading a non-constant-effect. The adjusted point estimate of the mean outcome variance ratio (treated to control group) is 0.89 (95% CI 0.81 to 0.97). Conclusions: We found that the outcome variance was more often smaller in the intervention group, suggesting that treated patients may end up pertaining more often to reference or “normality” values and thus would not require further precision medicine. However, this result may also be compatible with a reduced effect in some patients, which would require studying whether the effect merits enduring the side effects as well as the economic costs. We have shown that the comparison of variances is a useful but not definitive tool to asses if the design assumption of a constant effect holds.